Sulphonyloxazolamines as therapeutic active ingredients

ABSTRACT

The present invention relates to sulphonylexazolamines of general formula (I), wherein R 1 , R 2  represent independently from each other H, A, —(CH 2 ) n —Ar or alkenyl with 2-6 C atoms, R 1  and R 2  together also represent a mononuclear saturated heterocycle with 1-2 N, O and/or S atoms, Z is H, A, CF 3 , NO 2 , Hal, OH, OA, NH 2 , NHA or NH 2 . A represents alkyl with 1-6 C atoms, Ar is Z-monosubstituted or Z-disubstituted phenyl, Hal is F, Cl, Br, or L n is 1 or 2 of the physiologically acceptable salts or solvates thereof. Said sulphonyloxazolamines are used as therapeutic active ingredients. The invention also relates to the use of sulphonyloxazolamines as therapeutic active ingredients and/or to the production of pharmaceutical preparations to combat diseases of the central nervous system. The invention further relates to a pharmaceutical preparation and the production thereof.

This application is a 371 of PCT/EP99/09335 filed on Dec. 1, 1999.

The invention relates to sulfonyloxazolamines of the general formula I

in which

R¹, R² each independently of one another are H, A, —(CH₂)_(n)—Ar oralkenyl having 2 to 6 C atoms,

R¹ and R² together are also a mononuclear saturated heterocycle having 1to 2 N, O and/or S atoms,

Z, is H, A, CF₃, NO₂, Hal OH, OA, NH₂, NHA or NA₂,

A is alkyl having 1 to 6 C atoms,

Ar is phenyl which is mono- or di-substituted by Z,

Hal is F, Cl, Br or I,

n is 1 or 2,

or their physiologically acceptable salts or solvates as therapeuticactive compounds.

The invention furthermore relates to the use of the sulfonyloxazolaminesof the general formula I as therapeutic active compounds.

The invention also relates to the use of the sulfonyloxazolamines of thegeneral formula I for the production of pharmaceutical preparations inthe control of disorders of the central nervous system.

Some compounds of the general formula I are known from various earlierpublications. Thus, the preparation of the compounds of the formula I isdescribed in V. A. Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991,57(4), 415-418 or V. A. Chervonyi et al., Zh. Org. Khim. 1988, 24 (2),453-4 corresponding to V. A. Chervonyi et al., J. Org. Chem. USSR (Engl.transl.) 1988, 24, 401. More detailed publications with respect to thepharmacological efficacy of the compounds of the formula I are notavailable in the prior art.

The invention was based on the object of finding novel useful propertiesof sulfonyloxazolamines, in particular those which confirm the compoundsto be therapeutic active compounds and/or can lead to the use of thesulfonyloxazolamines as therapeutic active compounds and/or to theproduction of pharmaceutical preparations.

It has been found that the compounds of the formula I and theirpharmacologically active salts surprisingly have a selective affinityfor 5-HT6 receptors, together with good tolerability. They exhibit5-HT6-antagonistic or 5-HT6 agonistic actions.

5-HT6 receptors form a subfamily of 5-HT receptors. The neurotransmitter5-hydroxytryptamine (5-HT), also known as serotonin, is an importantregulating neurotransmitter in the brain, whose actions are assisted bya a family of receptors which, at the current level of knowledge,contain 13 G protein-coupled receptors and an ion channel.

The greatest density of the serotonin S-HT6 receptors in the brain isfound in the olfactory tubercle, in the nucleus accumbens, in thestriatum, in the dentate gyrus and in the CA1-3 regions of thehippocampus. These regions are involved to a particular extent inpsychiatric disorders such as, for example, schizophrenia or depression.Moreover, At is known from animal experiments that the administration ox5-HT6 antisense oligonucleotides causes a behavioural syndrome whichcorresponds to that of dopamine agonists. Furthermore, hyperactivity ofthe dopaminergic neurotransmitter system in schizophrenia (dopaminehypothesis of schizophrenia) is pathophysiologically confirmed. However,dysfunctions of the dopamine system in various forms of depression havebeen demonstrated. Of the established or alternatively newertherapeutics which are employed in clinical practice for the treatmentof these psychiatric disorders, a large number moreover bind to the5-HT6 receptor. The atypical neuroleptics (e.g. clozapine) and thetricyclic antidepressants (e.g. amitriptyline) may be mentioned here inparticular.

Moreover, it was found in animal experimental investigations that 5-HT6receptors in the brain control cholinergic neurotransmission.Cholinergics are employed in disorders with memory disturbances such as,for example, Alzheimer's disease.

For these reasons, it can be concluded that there is an involvement ofthe 5-HT6 receptor in psychiatric and neurological disorders such as,preferably, schizophrenia, depression and Alzheimer's.

The compounds of the formula I and their physiologically acceptablesalts are therefore suitable as therapeutic active compounds fordisorders of the central nervous system. The compounds of the formula Iand their physiologically acceptable salts or solvates are particularlysuitable for the treatment of psychoses, schizophrenia, manic depression(B. L. Roth et al., J. Pharmacol. E. Ther. 1994, 268, 1403-1410),depression (D. R. Sibley et al., Mol. Pharmacol. 1993, 43, 320-327),neurological disorders (A. Bourson et al., J. Pharmacol. Exp. Ther.1995, 274, 173-180), memory disorders, Parkinson's disease, amyotrophiclateral sclerosis, Alzheimer's disease, Huntington's disease (A. J.Sleight et al., Neurotransmissions 1995, 11, 1-5), bulimia, anorexianervosa or other eating disorders, compulsive acts or of premenstrualsyndrome.

The invention relates to the compounds of the formula I or theirphysiologically acceptable salts or solvates as therapeutic activecompounds.

The invention relates to the use of compounds of the formula I or theirphysiologically acceptable salts or solvates as therapeutic activecompounds.

The invention furthermore relates to the use of compounds of the formulaI or their physiologically acceptable salts or solvates as therapeuticactive compounds or disorders of the central nervous system.

Solvates of the compounds of the formula I are understood as meaningadducts of inert solvent molecules to the compounds of the formula I,which are formed on account of their mutual force of attraction.Solvates are, for example, mono- or dihydrates or alcoholates.

For all radicals which occur more than once, such as, for example, Z, itholds true that their meanings are independent of one another.

Above and below, the radicals and parameters R¹, R², Z and n have themeanings indicated in the formulae I to VI, if not expressly statedotherwise.

In the above formulae, A is alkyl, is linear or branched, and has 1 to6, preferably 1, 2, 3 or 4, C atoms. A is preferably methyl, furthermoreethyl, propyl, butyl, isobutyl, sec-butyl or tert-butyl, in additionalso pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl or hexyl. Methyl is particularly preferred.

Alkenyl is preferably allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl,in addition is preferably 4-pentenyl, isopentenyl or 5-hexenyl. Allyl isparticularly preferred for alkenyl.

Ar is preferably phenyl which is mono- or disubstituted by Z, where Zcan be X, A, CF₃, NO₂, Hal, OH, OA, NE₂, NHA or NA₂.

Ar is therefore preferably phenyl, o-, m- or p-methylphenyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-ter-butylphenyl, o-, m- or p-aminophenyl, o-, m- orp-N,N-dimethylaminophenyl, o-, m- or p-nitrophenyl, o-, m- orp-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl,o-, m-, p-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- orp-chlorophenyl, o-, m- or p-bromopheryl, furthermore preferably 2,3-,2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dimethoxyphenyl.

Phenyl, o- or p-methylphenyl, o- or p-chlorophenyl, p-bromophenyl,p-methoxyphenyl or 2,4-dichlorophenyl is particularly preferred for Ar.

In —(CH₂)_(n)—Ar, Ar has one of the preferred meanings indicatedbeforehand, where n can be 1 or 2. Benzyl is particularly preferred for—(C₂)_(n)—Ar.

Hal is preferably fluorine, chlorine or bromine.

Z is H, A, CF₃, NO₂, Hal, OH, OA, NH₂, NHA or NA₂, where A and Hal haveone of the preferred meanings indicated beforehand. H, methyl, chlorine,bromine or methoxy is particularly preferred for Z.

n is preferably 1 or 2, particularly preferably 1.

R¹ and R² are, independently of one another, H, A —(CH₂)_(n)—Ar oralkenyl having 2 to 6 C atoms, where A, Ar, alkenyl and n have one ofthe, preferred or particularly preferred meanings indicated beforehand.

In addition, R¹ and R² together are also a mononuclear saturatedheterocycle having 1 to 2 N, O and/or S atoms.

R₁ and R² together are preferably tetrahydro-2- or -3-furyl,1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 1-, 2- or3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, tetrahydro-1-, -3-or -4-pyrazolyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or4-perhydroazepinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl or 1-, 2- or3-piperazinyl. 1-Piperidinyl or 4-morpholinyl is particularly preferredfor R¹ and R² together.

For the subject of the invention, of the therapeutic active compounds ofthe formula I or their physiologically acceptable salts or solvates, ofthe use of the compounds of the formula I or their physiologicallyacceptable salts or solvates as therapeutic active compounds or of theproduction of a pharmaceutical preparation for the treatment ofdisorders of the central nervous system, in particular those compoundsof the formula I are preferred in which at least one of the radicalsmentioned has one of the preferred or particularly preferred meaningsindicated above. Some preferred groups of compounds can be expressed bythe following subformulae Ia to Ic, which correspond to the formula Iand in which the radicals not described in greater detail have themeaning indicated in the formula I, but in which

in Ia R¹ and R² in each case independently of one another are H, A,—(CH₂)_(n)—Ar or alkenyl having 2 to 6 C atoms;

in Ib R¹ and R² in formula I together are 1-piperidinyl;

or

in Ic R¹ and R² in formula I together are 4-morpholinyl;

The following compounds of the formulae Ia, Ib and Ic are particularlypreferred for use according to claim 1:

dimethyl-[2-phenyl-4-(toluene-4-sulfonyl)oxazol-5-yl]-amine;

[2-(2,4-dichlorophenyl)-4-(toluene-4-sulfonyl)oxazol-5-yl]dimethylamine;

benzyl-[2-(2,4-dichlorophenyl)-4-(toluene-4-sulfonyl)-oxazol-5-yl]amine;

methyl-[4-(toluene-4-sulfonyl)-2-p-tolyloxazol-5-yl]amine;

benzyl-[4-(4-chlorobenzenesulfonyl)-2-(2,4-dichlorophenyl)oxazol-5-yl]amine;

(4-benzenesulfonyl-2-m-tolyloxazol-5-yl)benzylamize;

[4-(4-chlorobenzenesulfonyl)-2-p-tolyloxazol-5-yl]-dimethylamine;

(4-benzenesulfonyl-2-o-tolyloxazol-5-yl)methylamine;

benzyl-[4-(4-chlorobenzenesulfonyl)-2-(2-chlorophenyl)-oxazol-5-yl]amine;

[4-benzenesulfonyl-2-(2,4-dichlorophenyl)oxazol-5-yl]-benzylamine;

[4-benzenesulfonyl-2-(2,4-dichlorophenyl)oxazol-5-yl]-dimethylamine;

[4-benzenesulfonyl-2-(2-chlorophenyl)oxazol-5-yl]-dimethylamine;

1-[2-(2,4-dichlorophenyl)-4-(toluene-4-sulfonyl)-oxazol-5-yl]piperidine;

1-[4-benzenesulfonyl-2-(2,4-dichlorophenyl)oxazol-5-yl]piperidine;

1-[4-benzenesulfonyl-2-(2-chlorophenyl)oxazol-5-yl]-piperidine;

4-[4-(toluene-4-sulfonyl)-2-p-tolyloxazol-5-yl]-morpholine;

4-[4-(4-chlorobenzenesulfonyl)-2-p-tolyloxazol-5-yl]-morpholine;

4-[4-(4-chlorobenzenesulfonyl)-2-phenyloxazol-5-yl]-morpholine;

4-[4-(4-benzenesulfonyl)-2-(4-bromophenyl)oxazol-5-yl]-morpholine;

4-[4-(4-benzenesulfonyl)-2-m-tolyloxazol-5-yl]-morpholine;

4-[4-(4-benzenesulfonyl)-2-(4-methoxyphenyl)oxazol-5-yl]morpholine;

4-[4-(4-benzenesulfonyl)-2-phenyloxazol-5-yl]-morpholine;

allyl-(4-benzenesulfonyl-2-phenyloxazol-5-yl)amine,

4-[4-benzenesulfonyl-2-(2-chlorophenyl)oxazol-5-yl]-morpholine;

(4-benzenesulfonyl-2-phenyloxazol-5-yl)dimethylamine;

(4-benzenesulfonyl-2-m-tolyloxazol-5-yl)dimethylamine;

benzyl-[2-phenyl-4-(toluene-4-sulfonyl)oxazol-5-yl]-amine and

benzyl-[4-(toluene-4-sulfonyl)-2-m-tolyloxazol-5-yl]-amine.

In relation to formula Ia, the following known compounds are preferredfor use as therapeutic active compounds:

dimethyl-[2-phenyl-4-(toluene-4-sulfonyl)oxazol-5-yl]-amine;

[2-(2,4-dichlorophenyl)-4-(toluene-4-sulfonyl)oxazol-5-yl]dimethylamine;

benzyl-[2-(2,4-dichlorophenyl)-4-(toluene-4-sulfonyl)-oxazol-5-yl]amine;

methyl-[4-(toluene-4-sulfonyl)-2-p-tolyloxazol-5-yl]-amine;

benzyl-[4-(4-chlorobenzenesulfonyl)-2-(2,4-dichloro-phenyl)oxazol-5-yl]amine;

(4-benzenesulfonyl-2-m-tolyloxazol-5-yl)benzylamine;

[4-(4-chlorobenzenesulfonyl)-2-p-tolyloxazol-5-yl]-dimethylamine;

(4-benzenesulfonyl-2-o-tolyloxazol-5-yl)methylamine;

benzyl-[4-(4-chlorobenzenesulfonyl)-2-(2-chlorophenyl)-oxazol-5-yl]amine;

[4-benzenesulfonyl-2-(2,4-dichlorophenyl)oxazol-5-yl]-benzylamine;

allyl-(4-benzenesulfonyl-2-phenyloxazol-5-yl)amine;

(4-benzenesulfonyl-2-phenyloxazol-5-yl)dimethylamine;

(4-benzenesulfonyl-2-m-tolyloxazol-5-yl)dimethylamine;

benzyl-[2-phenyl-4-(toluene-4-sulfonyl)oxazol-5-yl]-amine;

benzyl-[4-(toluene-4-sulfonyl)-2-m-tolyloxazol-5-yl]-amine;

[4-benzenesulfonyl-2-(2,4-dichloropnenyl)oxazol-5-yl]dimethylamine and

[4-benzenesulfonyl-2-(2-chlorophenyl)oxazol-5-yl]-dimethylamine.

In relation to formula Ib, the following known compounds are preferredfor use as therapeutic active compounds:

1-[2-(2,4-dichlorophenyl)-4-(toluene-4-sulfonyl)-oxazol-5-yl]piperidine;

1-[4-benzenesulfonyl-2-(2,4-dichlorophenyl)oxazol-5-yl]piperidine and

1-[4-benzenesulfonyl-2-(2-chlorophenyl)oxazol-5-yl]-piperidine.

In relation to formula Ic, the following known compounds are preferredfor use as therapeutic active compounds:

4-[4-(toluene-4-sulfonyl)-2-p-tolyloxazol-5-yl]-morpholine;

4-[4-(4-chlorobenzenesulfonyl)-2-p-tolyloxazol-5-yl]-morpholine;

4-[4-(4-chlorobenzenesulfonyl)-2-phenyloxazol-5-yl]-morpholine;

4-[4-(4-benzenesulfonyl)-2-(4-bromophenyl)oxazol-5-yl]morpholine;

4-[4-(4-benzenesulfonyl)-2-m-tolyloxazol-5-yl]-morpholine;

4-[4-benzenesulfonyl-2-(2-chlorophenyl)oxazol-5-yl]-morpholine;

4-[4-(4-benzenesulfonyl)-2-(4-methoxyphenyl)oxazol-5-yl]morpholine and

4-[4-(4-benzenesulfonyl)-2-phenyloxazol-5-yl]-morpholine.

The invention furthermore relates to the use of the following compounds,selected from the group

a) dimethyl-[2-phenyl-4-(toluene-4-sulfonyl)oxazol-5-yl]amine,

b)[2-(2,4-dichlorophenyl)-4-(toluene-4-sulfonyl)-oxazol-5-yl]dimethylamine,

c)benzyl-[4-(4-chlorobenzenesulfonyl)-2-(2-chlorophenyl)oxazol-5-yl]amine,

d) (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)-methylamine,

e)benzyl-[2-(2,4-dichlorophenyl)-4-(toluene-4-sulfonyl)oxazol-5-yl]amine,

f) [4-benzenesulfonyl-2-(2,4-dichlorophenyl)oxazol-5-yl]benzylamine,

g) [4-benzenesulfonyl-2-(2,4-dichlorophenyl)oxazol-5-yl]dimethylamine,

or one of their physiologically acceptable salts or solvates astherapeutic active compounds against disorders of the central nervoussystem.

The compounds of the formula I are generally commercially obtainable orcan be synthesized according to the following synthesis scheme (for thiscf. V. A. Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991, 57(4),415-418 or V. A. Chervonyi et al., Zh. Org. Khim. 1988, 24(2), 453-4,corresponding to V. A. Chervonyi et al., J. Org. Chem. USSR (Engl.transl.) 1988, 24, 401).

In the synthesis scheme shown beforehand, the starting material of theformula II is reacted with trichloroacetate to give the compound III.The reaction with thionyl chloride and subsequently with the sodiumsulfinate of the formula V generates an aryl vinyl sulfone of theformula VI, which cyclizes to give the sulfonyloxazolamines of theformula I by reaction with an amine of the formula VII. In thisconnection, the substituents Ar, Z, R¹ and R² of the formula II to VIIhave preferred or particularly preferred meanings as indicatedbeforehand.

The suitable reaction conditions of the reactions mentioned from thesynthesis scheme are known from the references V. A. Chervonyi et al.,Ukr. Khim. Zh. (Russ. Ed.) 1991, 57(4), 415-418 or V. A. Chervonyi etal., Zh. Org. Khim. 1988; 24(2), 453-4 corresponding to V. A. Chervonyiet al., J. Org. Chem. USSR (Engl. transl.) 1988, 24, 401, or fromstandard works such as, for example, Houben-Weyl, Methoden derorganischen Chemie [Methods of organic Chemistry], Georg-Thieme-Verlag,Stuttgart. In this case, use can also be made of variants which areknown per se, but not mentioned here in greater detail.

A base of the formula I can be converted into the associated acidaddition salt using an acid, for example by reaction of equivalentamounts of the base and of the acid in an inert solvent such as ethanoland subsequent evaporation. For this reaction, suitable acids are inparticular those which yield physiologically acceptable salts. Thusinorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalicacids such as hydrochloric acid or hydrobromic acid, phosphoric acidssuch as orthophosphoric acid, sulfamic acid, in addition organic acids,in particular aliphatic, alicyclic, araliphatic, aromatic orheterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids,e.g. formic acid, acetic acid, propionic acid, pivalic acid,diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaricacid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid,gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid,methane- or ethanesulfonic acid, p-toluenesulfonic acid,naphthalenemono- and disulfonic acids or lauryl sulfuric acid. Saltswith physiologically unacceptable acids, e.g. picrates, can be used forthe isolation and/or purification of the compounds of the formula I.

The binding of the compounds of the formula I to 5-HT6 receptors wasdetermined as follows: The substances to be tested were dissolved inDMSO at a concentration of 1 mM and diluted to the desiredconcentrations (0.1 nM to 10 μM) using test buffer (20 mM HEPES, 0.1%ascorbic acid, adjusted to pH 7.4 using NaOH).

20 μl of the respective substance solution were incubated at 37° C. for1 hour with 80 μl of ³H-LSD solution (TRK-1041, Amersham Pharmacia,Freiburg, spec. act. 80-90 Ci/mMol, 1 nM in the batch) and 100 μl ofmembrane suspension (5-HT6 receptors, RB-HS6, Biotrend, Cologne, 25-30μg of protein). The reaction mixture was filtered through GFB Filters(Whatman) which had been pretreated with 0.1% aqueous polyethyleneiminesolution for 1 hour. The filters were washed 3 times with 3 ml of testbuffer, the filters [sic] transferred to minivials and, after additionof Ultima Gold (Packard, Frankfurt), the radioactivity was determined ina liquid scintillation counter. The evaluation and IC₅₀ determinationwas carried out by means of in-house programs in RS1 (BBN SoftwareCorporation).

The compounds of the formula I have a selective affinity for 5-HT6receptors having an inhibition constant IC₅₀ of less than 4 μmol/l.

The invention furthermore relates to the use of the compounds of thegeneral formula I for the production of a pharmaceutical preparation forcontrolling disorders of the central nervous system.

The invention furthermore relates to the use of compounds of the generalformula I for the production of a pharmaceutical preparation for thetreatment of psychoses, schizophrenia, manic depression, depression,neurological disorders, memory disorders, Parkinson's disease,amyotrophic lateral sclerosis, Alzheimer's disease, Huntington'sdisease, bulimia, anorexia nervosa or other eating disorders, compulsiveacts or premenstrual syndrome.

The invention furthermore relates to pharmaceutical preparations for thecontrol of disorders of the central nervous system, comprising at leastone compound of the formula I or one of its physiologically acceptablesalts or solvates.

These preparations can be used as pharmaceuticals in human or veterinarymedicine. Possible vehicles are organic or inorganic substances whichare suitable Thor enteral (e.g. oral), or parerteral administration ortopical application and do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatin, carbohydrates suchas lactose or starch, magnesium stearate, talc or petroleum jelly.Tablets, pills, coated tablets, capsules, powders, granules, syrups,juices or drops, in particular, are used for oral administration,suppositories are used for rectal administration, solutions, preferablyoily or aqueous solutions, in addition suspensions, emulsions orimplants, are used for parenteral administration, and ointments, creamsor powders are used for topical application. The novel compounds canalso be lyophilized and the lyophilizates obtained used, for example,for the production of injection preparations. The preparations indicatedcan be sterilized and/or can contain excipients such as lubricants,preservatives, stabilizers and/or wetting agents, emulsifiers, salts forinfluencing the osmotic pressure, buffer substances, colorants,flavourings and/or other active compounds, e.g. one or more vitamins.

The invention also relates to a process for the production of thesepharmaceutical preparations, which is characterized in that a compoundof the formula I or one of its physiologically tolerable salts orsolvates is brought into a suitable dose for together with at least onesolid, liquid or semiliquid vehicle or excipient and, if appropriate, incombination with one or more other active compound.

The compounds of the formula I and their physiologically acceptablesalts or solvates can be employed for the control of disorders of thecentral nervous system.

The substances according to the invention are as a rule administeredhere in a dose of preferably between approximately 1 and 500 mg, inparticular between 5 and 100 mg, per dose unit. The daily dose ispreferably between approximately 0.02 and 10 mg/kg of body weight. Thespecific dose for each patient, however, depends on all sorts of,factors, for example on the efficacy of the specific compound employed,on the age, body weight, general state of health, sex, on the diet, onthe time and route of administration, and on the excretion rate,pharmaceutical combination and severity of the particular disorder towhich the therapy applies. Oral administration is preferred.

The following examples relate to pharmaceutical preparations:

EXAMPLE A

Injection vials

A solution of 100 g of an active compound of the formula I and 5 g ofdisodium hydrogerphosphate is adjusted to pH 6.5 in 3 l ofdouble-distilled water using 2N hydrochloric acid, sterile-filtered,filled into injection vials, lyophilized under sterile conditions andaseptically sealed. Each injection vial contains 5 mg of activecompound.

EXAMPLE B

Suppositories

A mixture of 20 g of an active compound of the formula I is fused with100 g of soya lecithin and 1400 g of cocoa butter, poured into mouldsand allowed to cool, Each suppository contains 20 mg of active compound.

EXAMPLE C

Solution

A solution of 1 g of an active compound of the formula I, 9.38 g ofNaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 g of benzalkoniumchloride in 940 ml of double-distilled water is prepared. It is adjustedto pH 6.8, made up to 1 l and sterilizes by irradiation. This solutioncan be used in the form of eye drops.

EXAMPLE D

Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g ofpetroleum jelly under aseptic conditions

EXAMPLE E

Tablets

A mixture of 1 kg of active compound of the formula I, 4 kg of lactose,1.2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearateis compressed to give tablets in a customary manner such that eachtablet contains 10 mg of active compound.

EXAMPLE F

Coated tablets

Analogously to Example E, tablets are pressed sad are then coated in acustomary manner with a coating of sucrose, potato starch, talc,tragacanth and colorant.

EXAMPLE G

Capsules

2 kg of active compound of the formula I are filled into hard gelatincapsules in a customary manner such that each capsule contains 20 mg ofthe active compound.

EXAMPLE H

Ampoules

A solution of 1 kg of active compound of the formula I in 60 ml ofdouble-distilled water is sterile-filtered, filled into ampoules,lyophilized under sterile conditions and aseptically sealed. Eachampoule contains 10 mg of active compound.

What is claimed is:
 1. A compound of formula I′

in, which R¹, R² each independently of one another are H, A,—(CH₂)_(n)—Ar or alkenyl having 2 to 6 atoms, R¹ and R² together arealso a mononuclear saturated heterocycle having 1 or 2 N, O and/or Satoms, Z is CF₃, NO₂, Hal, OH, NH₂, NHA or NA₂, A is alkyl having 1 to 6C atoms, Ar is phenyl which is mono- or disubstituted by Z, Hal is F,Cl, Br or I, n is 1 or 2 or a physiologically acceptable salt or solvatethereof.
 2. A method for treating a disorder of the central nervoussystem, comprising administering an effective amount of a compound offormula I to a patient in need thereof

in, which R¹, R² each independently of one another are H, A,—(CH₂)_(n)—Ar or alkenyl having 2 to 6 atoms, R¹ and R² together arealso a mononuclear saturated heterocycle having 1 or 2 N, O and/or Satoms, Z is H, A, CF₃, NO₂, Hal, OH, NH₂, NHA or NA₂, A is alkyl having1 to 6 C atoms, Ar is phenyl which is mono- or disubstituted by Z, Halis F, Cl, Br or I, n is 1 or
 2. 3. A method for the treatment ofpsychoses, schizophrenia, manic depression, depression, neurologicaldisorders, memory disorders, Parkinson's disease, amyotrophic lateralsclerosis, Alzheimer's disease, Huntington's disease, bulimia, anorexianervosa, eating disorders, compulsive acts or premenstrual syndrome,comprising administering an effective amount of a compound of formula Ito patient in need thereof

in, which R¹, R² each independently of one another are H, A,—(CH₂)_(n)—Ar or alkenyl having 2 to 6 atoms, R¹ and R² together arealso a mononuclear saturated heterocycle having 1 or 2 N, O and/or Satoms, Z is H, A, CF₃, NO₂, Hal, OH, NH₂, NHA or NA₂, A is alkyl having1 to 6 C atoms, Ar is phenyl which is mono- or disubstituted by Z, Halis F, Cl, Br or I, n is 1 or
 2. 4. A pharmaceutical composition,comprising a compound of formula I

in, which R¹, R² each independently of one another are H, A,—(CH₂)_(n)—Ar or alkenyl having 2 to 6 atoms, R¹ and R² together arealso a mononuclear saturated heterocycle having 1 or 2 N, O and/or Satoms, Z is H, A, CF₃, NO₂, Hal, OH, NH₂, NHA or NA₂, A is alkyl having1 to 6 C atoms, Ar is phenyl which is mono- or disubstituted by Z, Halis F, Cl, Br or I, n is 1 or 2 and a pharmaceutically acceptablecarrier.
 5. A process for the production of a pharmaceutical compositionaccording to claim 4, comprising bringing a compound of the formula I orone of its physiologically tolerable salts or solvates into a suitabledose form together with at least one solid, liquid or semiliquid vehicleor excipient and, optionally, one or more other active compounds.
 6. Amethod for treating a disease mediated by 5-HT6 receptors, comprisingadministering an effective amount of a compound of formula I to patientin need thereof

in, which R¹, R² each independently of one another are H, A,—(CH₂)_(n)—Ar or alkenyl having 2 to 6 atoms, R¹ and R² together arealso a mononuclear saturated heterocycle having 1 or 2 N, O and/or Satoms, Z is H, CF₃, NO₂, Hal, OH, NH₂, NHA or NA₂, A is alkyl having 1to 6 C atoms, Ar phenyl which is mono- or disubstituted by Z, Hal is F,Cl, Br or I, n is 1 or
 2. 7. A method according to claim 6, comprisingadministering a)dimethyl-[2-phenyl-4-(toluene-4-sulfonyl)oxazol-5-yl]amine, b)[2-(2,4-dichlorophenyl)-4-(toluene-4-sulfonyl)oxazol-5-yl]dimethylamine,c)benzyl-[4-(4-cholorbenzenesulfonyl)-2-(2-chlorophenyl)oxazol-5-yl]amine,d) (4-benzenesulfonyl-2-o-tolyloxazol-5-yl)-methylamine, e)benzyl-[2-(2,4dichlorophenyl)-4-(toluene-4-sulfonyl)oxazol-5-yl]amine,f) [4-benzenusulfonyl-2-(2-,4dichlorophenyl)oxazol-5-yl]benzylamine, org) [4-benzenusulfonyl-2-(2-,4dichlorophenyl)oxazol-5-yl]dimethylamine.